The biological clock, the endothelium, and vascular remodeling Circadian rhythms are daily body rhythms that oscillate with a 24-hour period. A discrete signaling pathway termed `the biological clock' is the molecular basis of these daily rhythms. We have found that blood vessels contain a functional biological clock, including the critical clock components, Bmal1, Clock, Period, and Cryptochrome genes. Moreover, the biological clock is expressed within the endothelium of blood vessels, ideally positioned to modify endothelial signaling and vascular function. The central hypothesis of this application is that the biological clock has a local function within the vasculature to influence endothelial signaling and vascular remodeling. In the current application we present new evidence demonstrating that mice with disruption of the Bmal1 gene (Bmal1-KO), an essential component of the circadian clock, exhibit endothelial dysfunction, thrombosis, and impaired vascular remodeling. Furthermore, we demonstrate that Akt signaling, a key pathway in the regulation of endothelial function, is severely attenuated in Bmal1-KO mice. Based on these preliminary results, we hypothesize that Bmal1 is a novel regulator of endothelial signaling, vascular function, and vascular remodeling. To test this hypothesis, three specific aims are proposed. In the first aim, the regulation of the circadian clock will be studied in basal and flow-altered conditions. In the second aim, the physiologic and pathologic sequelae that impair vascular remodeling in Bmal1-KO and Clock mutant mice will be determined through analysis of blood vessel histomorphometry and cardiovascular hemodynamics. In the final aim, the molecular mechanisms through which Bmal1 regulates endothelial signaling will be determined through biochemical analysis of blood vessels in Bmal1-KO mice and in cultured endothelial cells having RNA interference to Bmal1. This work may improve our current understanding of the elevated cardiovascular risk associated with shift work, long-distance travel, and morning arousal, and provide new mechanistic insight into the development of vascular disease. PUBLIC HEALTH RELEVANCE The biological clock, the endothelium, and vascular remodeling Cardiovascular disease is the leading cause of death for both men and women in the United States and the world. There is a profound pattern in the time of day at which the death occurs. It is in the morning, when the endothelium is most vulnerable and blood pressure surges that stroke and heart attack most frequently happen. Thus, there exists a pattern of timing in cardiovascular biology and disease that follows a precise circadian rhythm. The molecular mechanism that underlies biological timing the circadian/biological clock is expressed throughout the body, including blood vessels. This work may improve our current understanding of the elevated cardiovascular risk associated with shift work, long-distance travel, and morning arousal, and provide new mechanistic insight into the development of vascular disease. [unreadable] [unreadable] [unreadable]